Gene expression profiling of aging reveals activation of a p53-mediated transcriptional program

被引:135
作者
Edwards, Michael G.
Anderson, Rozalyn M.
Yuan, Ming
Kendziorski, Christina M.
Weindruch, Richard
Prolla, Tomas A. [1 ]
机构
[1] Univ Wisconsin, Dept Genet & Med Genet, Madison, WI 53706 USA
[2] Univ Wisconsin, Vet Adm Hosp, Madison, WI USA
[3] Georgia Inst Technol, Sch Ind & Syst Engn, Atlanta, GA 30332 USA
[4] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI USA
[5] Univ Wisconsin, Dept Med, Madison, WI USA
[6] Univ Wisconsin, Wisconsin Reg Primate Res Ctr, Madison, WI USA
关键词
SKELETAL-MUSCLE; CALORIC RESTRICTION; OXIDATIVE DAMAGE; LIFE-SPAN; MOUSE DEVELOPMENT; DNA-DAMAGE; AGE; P53; CANCER; APOPTOSIS;
D O I
10.1186/1471-2164-8-80
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 [微生物学]; 090105 [作物生产系统与生态工程];
摘要
Background: Aging has been associated with widespread changes at the gene expression level in multiple mammalian tissues. We have used high density oligonucleotide arrays and novel statistical methods to identify specific transcriptional classes that may uncover biological processes that play a central role in mammalian aging. Results: We identified 712 transcripts that are differentially expressed in young ( 5 month old) and old (25-month old) mouse skeletal muscle. Caloric restriction (CR) completely or partially reversed 87% of the changes in expression. Examination of individual genes revealed a transcriptional profile indicative of increased p53 activity in the older muscle. To determine whether the increase in p53 activity is associated with transcriptional activation of apoptotic targets, we performed RT-PCR on four well known mediators of p53-induced apoptosis: puma, noxa, tnfrsf10b and bok. Expression levels for these proapoptotic genes increased significantly with age (P < 0.05), while CR significantly lowered expression levels for these genes as compared to control fed old mice (P < 0.05). Age-related induction of p53-related genes was observed in multiple tissues, but was not observed in young SOD2(+/-) and GPX4(+/-) mice, suggesting that oxidative stress does not induce the expression of these genes. Western blot analysis confirmed that protein levels for both p21 and GADD45a, two established transcriptional targets of p53, were higher in the older muscle tissue. Conclusion: These observations support a role for p53-mediated transcriptional program in mammalian aging and suggest that mechanisms other than reactive oxygen species are involved in the age-related transcriptional activation of p53 targets.
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页数:13
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